WO2007015744A1 - Composés thiényl bi-substitués et leur utilisation en tant que produits pharmaceutiques - Google Patents

Composés thiényl bi-substitués et leur utilisation en tant que produits pharmaceutiques Download PDF

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Publication number
WO2007015744A1
WO2007015744A1 PCT/US2006/027333 US2006027333W WO2007015744A1 WO 2007015744 A1 WO2007015744 A1 WO 2007015744A1 US 2006027333 W US2006027333 W US 2006027333W WO 2007015744 A1 WO2007015744 A1 WO 2007015744A1
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thiophene
carboxylic acid
propanoyl
amino
compound
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PCT/US2006/027333
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English (en)
Inventor
Ganfeng Cao
Chu-Biao Xue
Rajan Anand
Taisheng Huang
Ling Kong
Joseph Glenn
Hao Feng
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Incyte Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to modulators of the HM74a receptor, compositions thereof and methods of using the same.
  • Coronary artery disease is the number one cause of death in the United States (Nature Med 2002, 8:1209-1262). The initiation and progression of CAD involves a complex interplay between multiple physiological processes, including inflammation, lipid homeostasis, and insulin resistance/diabetes mellitus. Multiple clinical studies have now shown that the three primary components of plasma lipids, low-density lipoprotein (or LDL), high-density lipoproteins (or HDL), and triglycerides (or TGs), are causally associated with the propensity to develop atherosclerosis and CAD.
  • LDL low-density lipoprotein
  • HDL high-density lipoproteins
  • TGs triglycerides
  • drugs of the statin class are structurally similar to the molecule hydroxymethylglutaryl-coenzyme A (HMG-CoA), a biosynthetic precursor of cholesterol. These drugs are competitive inhibitors of the rate-limiting step of cholesterol biosynthesis catalyzed by HMG-CoA reductase.
  • HMG-CoA hydroxymethylglutaryl-coenzyme A
  • the statins lower LDL by upregulating the LDL receptor in the liver as well as by reducing the release of LDL into the circulation.
  • the statin class of lipid lowering agents can reduce plasma LDL concentrations by 30-60% and triglycerides by 25%, producing a reduction in the incidence of CAD by 25-60% and the risk of death by 30%.
  • Ezetimibe Zinc, Merck and Co.
  • Ezetimibe Zinc, Merck and Co.
  • Monotherapy with Ezetimibe typically lowers LDL by 20%, however when co-formulated with a statin, maximal reductions can exceed 60%. As with the statins, however, Ezetimibe has a negligible effect on plasma HDL.
  • PPAR alpha agonists are far superior in targeting this lipid endpoint.
  • the fibrates function by increasing lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apolipoprotein C-IH (an inhibitor of lipoprotein lipase activity).
  • apolipoprotein C-IH an inhibitor of lipoprotein lipase activity.
  • Fenofibrate Tricor, Abort
  • the fibrate class of lipid-lowering drugs also has a modest, but significant effect on both LDL (20% reduction) and HDL (10% increase).
  • This study also revealed a significantly reduced rate of intima-media thickness progression in subjects without detectable insulin resistance. This study indicates the incomplete cardio-protection that is offered by statin therapy and substantiates the utility of nicotinic acid in reducing overall cardiac risk in low-HDL patients.
  • HM74a high affinity GPCR
  • HSL hormone sensitive lipase
  • HM74a high affinity GPCR
  • adipocyte lipolytic output results in a reduction in circulating FFA and a corresponding reduction in hepatic TGs, very- low density LDL (VLDL), and LDL.
  • VLDL very- low density LDL
  • the increased levels of HDL arise from an effective reduction of cholesterol ester transfer protein activity due to decreased availability of VLDL acceptor molecules.
  • FFAs play fundamental roles in the regulation of glycemic control. It is now recognized that chronically elevated plasma FFA concentrations cause insulin resistance in muscle and liver, and impair insulin secretion (reviewed in Defronzo et al. Int. J. Clin. Prac. 2004, 58: 9-21). In muscle, acute elevations in plasma FFA concentrations can increase intramyocellular lipid content; this can have direct negative effects on insulin receptor signaling and glucose transport. In liver, increased plasma FFAs lead to accelerated lipid oxidation and acetyl-CoA accumulation, the later of which stimulates the rate-limiting steps for hepatic glucose production.
  • nicotinic acid as a hypolipidemic/FFA lowering agent
  • FFA release significant doses of nicotinic acid are required to impact FFA release and improve lipid parameters.
  • Immediate release (IR) nicotinic acid is often dosed at 3-9g/day in order to achieve efficacy, and ER nicotinic acid (Niaspan) is typically dosed between l-2g/day. These high doses drive the second issue with nicotinic acid therapy, hepatotoxicity.
  • IR immediate release
  • Niaspan ER nicotinic acid
  • NAM nicotinamide
  • nicotinic acid therapy often results in FFA rebound, a condition whereby free fatty acid levels are not adequately suppressed throughout the dosing regimen, resulting in a compensatory increase in adipose tissue lipolysis.
  • FFA rebound phenomenon With immediate release nicotinic acid, this rebound phenomenon is so great that daily FFA AUCs are actually increased after therapy.
  • Such FFA excursions can lead to impaired glycemic control and elevated blood glucose levels, both of which have been shown to occur in some individuals after nicotinic acid therapy.
  • HM74a giving the importance of nicotinic acid in modulating (especially agonizing) HM74a receptor and its limitations, novel small molecules designed to mimic the mechanism of nicotinic acid's action on HM74a offer the possibility of achieving greater HDL, LDL, TG, and FFA efficacy while avoiding adverse effects such as hepatotoxicity and cutaneous flushing.
  • Such therapies are envisoned to have significant impact beyond dyslipidemia to include insulin resistance, hyperglycemia, and associated syndromes by virtue of their ability to more adequately reduce plasma FFA levels during the dosing interval.
  • the present invention is directed to these, as well as other, important ends.
  • the present invention provides, inter alia, compounds of Formula I:
  • the present invention further provides compositions comprising a compound of the invention and a pharmaceutically acceptable carrier.
  • the present invention further provides methods of modulating HM74a receptor with a compound of the invention.
  • the present invention further provides methods of agonizing HM74a receptor by contacting the HM74a receptor with a compound of the invention.
  • the present invention further provides methods of treating diseases associated with HM74a receptor.
  • the present invention further provides compounds of the invention for use in therapeutic methods of treating diseases associated with HM74a receptor.
  • the present invention further provides compounds of the invention for use in the preparation of a medicament for use in therapeutic methods of treating diseases associated with HM74a receptor.
  • the present invention provides, inter alia, compounds of Formula I:
  • ring A is thienyl
  • Q is COOH or tetrazolyl
  • X is CR la R 2a , NR 3 , 0, S, SO, or SO 2 ;
  • Y is carbocyclyl or heterocyclyl, each optionally substituted by 1, 2 or 3 R 4 ;
  • Z is aryl or heteroaryl, each optionally substituted by 1, 2 or 3 R 5 ;
  • R 1 , R 2 , R Ia , and R 2a are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, and C 2- to alkoxyalkyl;
  • R 3 is H or C 1-6 alkyl
  • R 4 and R 5 are independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, CM haloalkyl, Ci -4 haloalkoxy, Cy 1 , CN, NO 2 , 0R a , SR a , C(0)R b , C(0)NR c R d , C(O)OR a , 0C(0)R b , 0C(0)NR c R d , NR c R d C(O)NR c R d , NR c R d , NR c C(0)R b , NR c C(0)0R a , S(O)R b , S(0)NR c R d , S(O) 2 R b , and S(0) 2 NR c R d , wherein said C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted by 1,
  • Cy 1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, Cj -4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, CN, NO 2 , 0R a' , SR a> , C(O)R b> , C(0)NR c R d' , C(0)0R a' , OC(O)R b' ,
  • R a and R a are independently selected from H, Q -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, (Ci -6 alkoxy)-C 1-6 alkyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, and heterocycloalkylalkyl;
  • R b and R b are independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl;
  • R c and R c> are independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, arylalkyl, and cycloalkylalkyl; and R d and R d are independently selected from H, C 1-O alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2 ⁇ alkynyl, aryl, cycloalkyl, arylalkyl, and cycloalkylalkyl; or R c and R d together with the N atom to which they are attached form a A-, 5-, 6- or 7-membered heterocycloalkyl group; or R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or
  • Q is COOH.
  • X is CR la R 2a or O. In some embodiments, X is CR la R 2a . In some embodiments, X is CH 2 .
  • X is O.
  • Y is aryl or heteroaryl, each optionally substituted by 1, 2, or 3 R 4 .
  • Y is phenyl or a 5- or 6-membered heteroaryl, each optionally substituted by 1 , 2, or 3 R 4 .
  • Y is phenyl or a 6-membered heteroaryl, each optionally substituted by 1, 2, or 3 R 4 .
  • Y is a 5-membered heteroaryl optionally substituted by 1, 2, or 3 R 4 . In some embodiments:
  • Y is:
  • U 1 is N or CH; U 2 and U 3 are independently selected from N and CH;
  • U 4 is NH, O, or S; and m, ml, m2, m3, and n are independently selected from 0, 1, 2 or 3.
  • Y is:
  • U 1 is N or CH
  • U 2 and U 3 are independently selected from N and CH; U 4 is NH, O, or S; and m, ml, m2, m3, and n are independently selected from 0, 1, 2 or 3.
  • Y is phenyl, pyridyl, thienyl, or l,2,4-oxadiazol-5-yl, each optionally substituted by 1, 2, or 3 R 4 . In some embodiments, Y is phenyl, pyridyl, or l,2,4-oxadiazol-5-yl, each optionally substituted by 1, 2, or 3 R 4 .
  • Z is phenyl or a 5- or 6-membered heteroaryl, each optionally substituted by 1, 2, or 3 R 5 .
  • Z is phenyl or a 6-membered heteroaryl, each optionally substituted by 1 , 2, or 3 R 5 .
  • Z is a 5-membered heteroaryl optionally substituted by 1, 2, or 3 R 5 .
  • Z is phenyl, furyl, thienyl, thiazolyl, pyridyl, pyrimidinyl or pyrazinyl, each optionally substituted by 1, 2, or 3 R 5 .
  • R 1 and R 2 are independently selected from H and C 1-6 alkyl.
  • R 1 and R 2 are both H.
  • R 4 and R 5 are independently selected from halo, CN, NO 2 , OH, C 1-S alkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, hydroxylalkyl, CM haloalkyl, Q ⁇ haloalkoxy, C 1-6 alkoxy, C 2-12 alkoxyalkyl, C 1-6 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, arylalkylsulfonyl, and heteroarylalkylsulfonyl.
  • the compounds of the present invention have Formula II:
  • the compounds of the present invention have Formula HI:
  • the compounds of the present invention have Formula IV:
  • C 1-6 alkyl is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • each variable can be a different moiety selected from the Markush group defining the variable.
  • the two R groups can represent different moieties selected from the
  • substituent R can occur s number of times on the ring, and R can be a different moiety at each occurrence.
  • variable W be defined to include hydrogens, such as when W is said to be CH 2 , NH, etc.
  • any floating substituent such as R in the above example can replace a hydrogen of the W variable as well as a hydrogen in any other non-variable component of the ring.
  • n-membered where n is an integer typically describes the number of ring- forming atoms in a moiety where the number of ring-forming atoms is n.
  • piperidinyl is an example of a 6-membered heterocycloalkyl ring
  • 1,2,3,4-tetrahydro- naphthalene is an example of a 10-membered cycloalkyl group.
  • alkyl is meant to refer to a saturated hydrocarbon group which is straight-chained or branched.
  • Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n- pentyl, isopentyl, neopentyl), and the like.
  • An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.
  • alkenyl refers to an alkyl group having one or more double carbon- carbon bonds.
  • Example alkenyl groups include ethenyl, propenyl, and the like.
  • alkenylenyl refers to a divalent linking alkenyl group.
  • alkynyl refers to an alkyl group having one or more triple carbon- carbon bonds.
  • Example alkynyl groups include ethynyl, propynyl, and the like.
  • alkynylenyl refers to a divalent linking alkynyl group.
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 CI 5 , and the like.
  • Carbocyclyl groups are saturated (i.e., containing no double or triple bonds) or unsaturated (i.e., containing one or more double or triple bonds) cyclic hydrocarbon moieties.
  • Carbocyclyl groups can be mono- , poly- (e.g., 2, 3 or 4 fused rings).
  • Example carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, norbornyl, norpinyl, norcarnyl, adamantyl, phenyl, and the like.
  • Carbocyclyl groups can be aromatic (e.g., "aryl") or non- aromatic (e.g., "cycloalkyl”). In some embodiments, carbocyclyl groups can have from about 3 to about 30 carbon atoms, about 3 to about 20, about 3 to about 10, or about 3 to about 7 ring-forming carbon atoms.
  • aryl refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms.
  • cycloalkyl refers to non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spiro ring systems.
  • Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfide
  • Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like.
  • cycloalkyl moieties that have one or more aromatic rings (can be aryl or heteroaryl) fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of pentane, pentene, hexane, and the like.
  • heterocyclyl or “heterocycle” refers to a saturated or unsaturated cyclic hydrocarbon wherein one or more of the ring-forming carbon atoms of the cyclic hydrocarbon is replaced by a heteroatom such as O, S, or N.
  • Heterocyclyl groups can be aromatic (e.g., “heteroaryl") or non-aromatic (e.g., "heterocycloalkyl”)- Heterocyclyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems.
  • Heterocyclyl groups can be characterized as having 3-14 or 3-7 ring-forming atoms.
  • heterocyclyl groups can contain, in addition to at least one heteroatom, from about 1 to about 13, about 2 to about 10, or about 2 to about 7 carbon atoms and can be attached through a carbon atom or heteroatom.
  • any ring-forming carbon or heteroatom can be oxidized (e.g., have an oxo or sulfido substituent), or a nitrogen atom can be quaternized.
  • heterocyclyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-l,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like, as well as any of the groups listed below for "heteroaryl” and "heterocycloalkyl.”
  • heterocycles include pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,
  • heterocycles include azetidin- 1-yl, 2,5-dihydro-lH-pyrrol-l-yl, piperindin-lyl, piperazin-1-yl, pyrrolidin-1-yl, isoquinol-2- yl, pyridin-1-yl, 3,6-dihydropyridin-l-yl, 2,3-dihydroindol-l-yl, l,3,4,9-tetrahydrocarbolin-2- yl, thieno[2,3-c]pyridin-6-yl, 3,4,10,10a-tetrahydro-lH-pyrazino[l,2-a]indol-2-yl, l,2,4,4a,5,6-hexahydro-pyrazino[l,2-a]quinolin-3-yl, pyrazino[l,2-a]quinolin-3-yl, diazepan- 1-yl, 1 ,4,5,
  • heteroaryl refers to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen.
  • Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems.
  • heteroaryl groups include without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,, and the like.
  • the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.
  • heterocycloalkyl refers to non-aromatic heterocycles including cyclized alkyl, alkenyl, and alkynyl groups where one or more of the ring-forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom.
  • Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spiro ring systems.
  • Example "heterocycloalkyl” groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-l,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like.
  • Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido.
  • moieties that have one or more aromatic rings can be aryl or heteroaryl) fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl, 4,5,6,7- tetrahydrothieno[2,3-c]pyridinyl, and benzo derivatives of heterocycles such as 1,2,3,4- tetrahydroisoquinyl, indolene and isoindolene groups.
  • the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.
  • alkoxy refers to an -O-alkyl group.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
  • haloalkoxy refers to an -O-haloalkyl group.
  • An example haloalkoxy group is OCF 3 .
  • alkoxy alkyl refers to alkyl substituted by alkoxy.
  • An example alkoxyalkyl group is methoxymethyl.
  • arylalkyl refers to alkyl substituted by aryl and "cycloalkylalkyl” refers to alkyl substituted by cycloalkyl.
  • An example arylalkyl group is benzyl, and an example cycloalkylalky is cyclopropylmethyl.
  • heteroarylalkyl refers to alkyl substituted by heteroaryl and “heterocycloalkylalkyl” refers to alkyl substituted by heterocycloalkyl.
  • An example heteroarylalkyl group is pyridin-3-yl-methyl, and an example heterocycloalkylalkyl group is piperidin-3-yl-ethyl.
  • Ci -6 alkylsulfonyl refers to (Ci -6 alkyl)-S(O) 2 -.
  • arylsulfonyl refers to aryl-S(O) 2 -.
  • heteroarylsulfonyl refers to heteroaryl-S(O) 2 -.
  • arylalkylsulfonyl refers to arylalkyl-S(O) 2 -.
  • heteroarylalkylsulfonyl refers to heteroarylalkyl-S(O) 2 -.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms.
  • An example method includes fractional recrystallizaion using a "chiral resolving acid" which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ⁇ -camphorsulfonic acid.
  • resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of ⁇ -methylbenzylamine (e.g., 5 and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine).
  • an optically active resolving agent e.g., dinitrobenzoylphenylglycine
  • Suitable elution solvent composition can be determined by one skilled in the art.
  • Compounds of the invention also include tautomeric forms, such as keto-enol tautomers.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.
  • the phrase "compounds of the invention" is meant to include not only the free base forms of the compounds disclosed herein but also their pharmaceutically acceptable salts.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
  • prodrugs refer to any covalently bonded carriers which release the active parent drug when administered to a mammalian subject.
  • Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include compounds wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention.
  • prodrugs of the present invention can include ester compounds of Formula I wherein Q is COOR and R is C 1-6 alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, or heteroarylalkyl, and the like.
  • the COOR esters would be expected to hydrolyze in vivo to form the corresponding acid moiety.
  • Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.
  • novel compounds of the present invention can be prepared in a variety of ways known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods as hereinafter described below, together with synthetic methods known in the art of synthetic organic chemistry or variations thereon as appreciated by those skilled in the art.
  • the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.
  • Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991, which is incorporated herein by reference in its entirety.
  • the reactions of the processes described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected.
  • the compounds of the invention can be prepared, for example, using the reaction pathways and techniques as described below.
  • compounds of formula 1-6 can be prepared using method A.
  • a compound of forumla 1-1 i.e., 3-(4-bromophenyl)propanoic acid or 3-(4- iodoophenyl)propanoic acid, can be converted to a more reactive species such as its corresponding acid chloride 1-2, using a chlorinating reagent such as either thionyl chloride or oxalyl chloride.
  • the acid chloride 1-2 can be coupled with methyl aminothiophenecarboxylate 1-3 to form an amide compound 1-4.
  • compounds of formula 1-4 can be generated by coupling of 1-1 with 1-3 through formation of a mixed anhydride of 1-1 with isobutyl chloroformate followed by using a coupling agent such as EDCI/HOBt.
  • the second aromatic ring (or heteroaromatic ring) at 4-position of the phenyl ring in 1-4 can be introduced by palladium catalyzed Suzuki coupling with a compound of ArB(OH) 2 such as an aryl boronic acid or by Negishi coupling with an organozinc halide compound of ArZnBr(Cl) such as an aryl zinc bromide, wherein Ar can be aryl, heteroaryl or substituted thereof.
  • the ester group on the resulting coupling intermediate 1-5 can be hydrolyzed in the presence of a base such as sodium hydroxide to provide a compound of formula 1-6.
  • a compound of formula 5-6 can be synthesized by method E.
  • 2,5-Dibromopyridine 4-1 is subjected to lithiation (for example, selective lithium-halogen exchange taking place at 2-position) in a solvent such as dichloromethane followed by an addition of N,N-dimethylformamide, to afford 5-bromopyridine-2 ⁇ carbaldehyde 5-1.
  • lithiation for example, selective lithium-halogen exchange taking place at 2-position
  • N,N-dimethylformamide N,N-dimethylformamide
  • Compounds of formula 6-5 can be obtained from the intermediate 6-4 by palladium catalyzed Suzuki coupling with a compound of ArB(OH) 2 such as an aryl boronic acid or by Negishi coupling with an organozinc halide compound ArZnBr(Cl) such as an aryl zinc bromide, wherein Ar can be aryl, heteroaryl or substituted thereof.
  • the ester group on the resulting compound 6-5 can be hydrolyzed in the presence of a base such as sodium hydroxide to provide a compound of formula 1-6.
  • Coupling the acid 7-3 with methyl aminothiophenecarboxylate 1-3 to afford an amide 7-5 can be accomplished by converting the acid to a more reactive species such as an acid chloride 7-4, followed by the addition of methyl aminothiophenecarboxylate 1-3.
  • the ester group on the resulting amide 7-5 can be hydrolyzed in the presence of a base such as sodium hydroxide to affords a compound of formula 7-6.
  • Compounds of the invention can modulate activity of the HM74a receptor.
  • modulate is meant to refer to an ability to increase or decrease activity of a receptor.
  • compounds of the invention can be used in methods of modulating HM74a receptor by contacting the receptor with any one or more of the compounds or compositions described herein.
  • compounds of the present invention can act as full or partial agonists of HM74a receptors.
  • the compounds of the invention can be used to modulate activity of HM74a receptors in an individual by administering a modulating amount of a compound of the invention.
  • the present invention further provides methods of treating diseases associated with the HM74a receptor, such as dyslipidemia, insulin resistance, hyperglycemia, and others, in an individual (e.g., patient) by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of the present invention or a pharmaceutical composition thereof.
  • Example diseases can include any disease, disorder or condition that is directly or indirectly linked to the HM74a receptor, such as diseases, disorders or conditions associated with low expression or low activity of HM74a receptor.
  • HM74a receptor-associated diseases include, but are not limited to, dyslipidemia, highly-active anti-retroviral therapy (HAART)-associated lipodystrophy, insulin resistance, diabetes such as type 2 diabetes mellitus, metabolic syndrome, atherosclerosis, coronary heart disease, stroke, obesity, elevated body mass index (BMI), elevated waist circumference, non-alcoholic fatty liver disease, hepatic steatosis, hypertension, and other pathologies, such as those (like many of the aforementioned) associated with elevated plasma FFAs.
  • HAART highly-active anti-retroviral therapy
  • dislipidemia refers to any one or more of the following diseases or conditions: low-HDL cholesterol, elevated cholesterol, elevated LDL cholesterol (including any combination of small, dense LDL, intermediate density lipoproteins, very-low density lipoproteins, and chylomicrons), elevated total cholesterol/HDL ratio, elevated plasma triglycerides, elevated circulating free fatty acid levels, and elevated lipoprotein (a).
  • the present invention provides methods of lowering cholesterol level, lowering LDL, lowering total cholesterol/HDL ratio, lowering plasma triglycerides, lowering circulating free fatty acid levels, lowering lipoprotein (a), or raising HDL cholesterol, in a mammal by administering an effective amount of a compound or composition herein to the mammal.
  • the term "cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo.
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in an organism such as a mammal.
  • the cell is an adipocyte, a pancreatic cell, a hepatocyte, neuron, or cell comprising the eye.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • "contacting" the HM74a receptor with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having the HM74a receptor, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the HM74a receptor.
  • the term "individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the phrase "therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;
  • inhibiting the disease for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and
  • ameliorating the disease for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
  • the compounds of the present invention can be used in combination with other enzyme or receptor modulators.
  • enzyme or receptor modulators include, but are not limited to, any one or more of the following: HMG-CoA reductase inhibitors (so- called statins), PPAR alpha agonists or selective modulators, PPAR gamma agonists or selective modulators (both TZD and non-TZD), PPAR delta agonists or selective modulators, PPAR alpha/gamma dual agonists, pan-PPAR agonists or selective modulators, glucocorticoid receptor antagonists or selective modulators, bile acid-binding resins, NPClLl receptor antagonists, cholesterol ester transfer protein inhibitors, apoA-I or synthetic apoA- I/HDL molecules, LXR agonists or selective modulators, FXR agonists or selective modulators, endothelial lipase inhibitors, hepatic lipase inhibitors, SR-BI modulators, estrogen receptor
  • the compounds of the invention can be administered in the form of pharmaceutical compositions.
  • These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral.
  • topical including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery
  • pulmonary e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal
  • ocular oral or parenteral.
  • Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions which contain, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10 % by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh.
  • the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • the compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • compositions administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
  • the compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered.
  • Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral adminstration. Some typical dose ranges are from about 1 ⁇ g/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose- response curves derived from in vitro or animal model test systems.
  • the compounds of the invention can also be formulated in combination with one or more additional active ingredients which can include any pharmaceutical agent such as antiviral agents, antibodies, immune suppressants, anti-inflammatory agents and the like, as well as any of the aforementioned enzyme or receptor modulators.
  • Another aspect of the present invention relates to fluorescent dye, spin lable, heavy metal or radio-labeled compounds of the invention that would be useful not only in imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the HM74a in tissue samples, including human, and for identifying HM74a ligands by binding of a labeled compound.
  • the present invention includes HM74a assays that contain such labeled compounds.
  • the present invention further includes isotopically-labeled compounds of the invention.
  • An “isotopically” or “radio-labeled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 1, 124 1, 125 I and 131 I.
  • the radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro receptor labeling and competition assays, compounds that incorporate 3 H, 14 C, 82 Br, 125 1 , 131 1, 35 S or will generally be most useful.
  • radio-imaging applications 11 C, 18 F, 125 1, 123 1, 124 1, 131 I, 75 Br, 76 Br or 77 Br will generally be most useful. It is understood that a “radio-labeled " or "labeled compound” is a compound that has incorporated at least one radionuclide. In some embodiments the radionuclide is selected from the group consisting of 3 H, 14 C, 125 1 , 35 S and 82 Br.
  • Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to compounds of the invention and are well known in the art.
  • a radio-labeled compound of the invention can be used in a screening assay to identify/evaluate compounds.
  • a newly synthesized or identified compound i.e., test compound
  • the ability of a test compound to compete with the radio-labeled compound for binding to the enzyme directly correlates to its binding affinity.
  • kits useful useful, for example, in the treatment or prevention of HM74a receptor-associated diseases or disorders, such as dyslipidemia, coronary heart disease and other diseases referred to herein which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • Methyl 2-[(4-bromophenoxy)acetyl]aminothiophene-3-carboxylate 100 mg, 0.27 mmol and phenylboronic acid (36 mg, 0.30 mmol) were dissolved in DMF (1.0 mL) before adding a 2 M solution of sodium carbonate in water (0.3 mL) and polymer-bound tetrakis(triphenylphosphine) palladium (0.5 mmol/g loading; 50 mg, 0.03 mmol).
  • the mixture was irradiated using microwave for 1 min at 150 0 C and filtered into a scintillation vial through a short pad of silica gel. The pad was washed with additional DMF (3 mL).
  • Example 31 2- ⁇ [3-(4-Pyridin-2-ylphenyl)propanoyl]amino ⁇ thiophene-3-carboxylic Acid a) 3-(4-Pyridin-2-ylphenyl)propanoic Acid.
  • Example 38 4-( ⁇ 3-[6-(2-Methoxyphenyl)pyridin-3-yl]propanoyl ⁇ amino)thiophene-3-carboxylic Acid a) ⁇ -Bromo-pyridineS-carbaldehyde.
  • Membranes were prepared from HEK293 cells transiently transfected with human
  • HM74a and G ⁇ 0 protein were performed in 384-well format in a volume of 50 ⁇ L per assay point. Serial dilutions of compounds were prepared in the assay buffer (20 niM HEPES pH. 7.4, 100 mM NaCl, 10 mM MgCl 2 , 10 mg/L saponin and 10 ⁇ M GDP) and mixed with membranes (2 ⁇ g per assay point) and 35 S GTP ⁇ S (Amersham, 0.3 nM) in the assay buffer.
  • Membranes were prepared from HEK293 cells transiently transfected with the human HM74a and G ⁇ 0 protein.
  • Wheat germ agglutinin SPA beads (Amersham) were weighed and suspended in the assay buffer (50 mM Tris-HCl, pH. 7.5, 1 mM MgCl 2 and 0.02% CHAPS). The beads were mixed with membrane (75 ⁇ g membrane/mg beads) at room temperature for 1 hr. The beads were spun down and washed once with buffer and then resuspended in buffer at 5 mg beads/ml. 2OnM of 3 H nicotinic acid was added to the beads and then mixed with compounds at (total vol. of 50 ⁇ L).
  • Nonspecific binding was determined by the inclusion of 100 ⁇ M nicotinic acid.
  • the binding mixtures were incubated at room temperature for overnight with agitation. Plates were centrifuged at 1500 g for 5 min and bound 3 H nicotinic acid was determined by counting on a TopCount scintillation counter.
  • An active compound according to this assay has an IC 50 of about 50 ⁇ M or less.
  • HEK293e cells transfected with human HM74a and G ⁇ i 6 DNA were seeded the day before the assay at 50,000 cells/well in 384-well plates.
  • Cells were washed once with IX HBSS and incubated with FLIPR Calcium 3 (Molecular Devices) dye in IX HBSS buffer containing 3 mM probenecid at 37 0 C and 5% CO 2 for 60 min.
  • FLIPR Calcium 3 Molecular Devices
  • Compounds were added to the cell plate and fluorescence changes due to G ⁇ i ⁇ 5 -mediated intracellular calcium response were measured.
  • An active compound according to this assay has an EC 50 of about 50 ⁇ M or less.
  • Example D cAMP assay CHO cells stably transfected with human HM74a are seeded at 7,500 cells/well in a
  • Example E 96-well plate in HAMS F12 medium with 10 % FBS. The plate is incubated overnight at 37 0 C and 5 % CO 2 .
  • the test compounds are prepared in a stimulation buffer containing IX HANKS, 20 mM HEPES, 5 ⁇ M forskolin, and 0.25 mM IBMX. The media from the cell plate is removed before adding 30 ⁇ L of the test compounds. After 30 minute incubation at 37 0 C and 5 % CO 2 , the cAMP level is assayed using HitHunter cAMP XS assay kit (DiscoverX, CA). IC5 0 determinations are based on compound inhibition relative to DMSO controls. An active compound according to this assay has an IC 50 of about 100 ⁇ M or less.
  • Preadipocytes purchased from Zen Bio are plated at 8.7 X 10 4 cells/well in 96-well plates, differentiated for 14 days and than mature adipocytes are assayed during days 15 through 21.
  • Adipocyte maturation is assessed by the presence of rounded cells with large lipid droplets in the cytoplasm. Following maturation, cells are washed and incubated overnight with IBMX (100 ⁇ M) and various concentrations of compound diluted in assay buffer containing a final DMSO concentration of 0.1%. After overnight culture, the glycerol concentration in the supernatants is determined with the Lipolysis Assay Kit purchased from
  • An active compound according to this assay has an IC 5O of about 10 ⁇ M or less.

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Abstract

La présente invention concerne des modulateurs du récepteur HM74a et leurs compositions pharmaceutiques. Les composés de l'invention peuvent être utiles dans le traitement de plusieurs maladies associées au récepteur HM74a.
PCT/US2006/027333 2005-07-21 2006-07-14 Composés thiényl bi-substitués et leur utilisation en tant que produits pharmaceutiques WO2007015744A1 (fr)

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WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US8624056B2 (en) 2007-12-21 2014-01-07 Fibrotech Therapeutics Pty Ltd Halogenated analogues of anti-fibrotic agents
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US9951087B2 (en) 2009-10-22 2018-04-24 Fibrotech Therapeutics Pty Ltd Fused ring analogues of anti-fibrotic agents
US11014873B2 (en) 2017-02-03 2021-05-25 Certa Therapeutics Pty Ltd. Anti-fibrotic compounds
CN115057829A (zh) * 2022-05-31 2022-09-16 甘肃联凯生物科技有限公司 一种高纯度唑丙酸的合成方法

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JP2009510016A (ja) * 2005-09-27 2009-03-12 エフ．ホフマン−ラ ロシュ アーゲー 糖尿病の治療のためのチオフェン誘導体
EP2010512A2 (fr) * 2006-04-11 2009-01-07 Merck & Co., Inc. Agonistes du récepteur de la niacine, compositions contenant de tels composés et méthodes de traitement
EP2010512A4 (fr) * 2006-04-11 2010-02-24 Merck & Co Inc Agonistes du récepteur de la niacine, compositions contenant de tels composés et méthodes de traitement
US8765812B2 (en) 2006-07-05 2014-07-01 Fibrotech Therapeutics Pty Ltd Therapeutic compounds
US9561201B2 (en) 2006-07-05 2017-02-07 Fibrotech Therapeutics Pty Ltd Therapeutic compounds
WO2008017381A1 (fr) 2006-08-08 2008-02-14 Sanofi-Aventis Imidazolidin-2,4-dione arylaminoaryl-alkyl-substituée, son procédé de fabrication, médicament contenant ce composé et son utilisation
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
DE102007063671A1 (de) 2007-11-13 2009-06-25 Sanofi-Aventis Deutschland Gmbh Neue kristalline Diphenylazetidinonhydrate, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
US8624056B2 (en) 2007-12-21 2014-01-07 Fibrotech Therapeutics Pty Ltd Halogenated analogues of anti-fibrotic agents
US9150563B2 (en) 2008-07-08 2015-10-06 Daiichi Sankyo Company, Limited Nitrogen-containing aromatic heterocyclyl compound
CN102149680A (zh) * 2008-07-08 2011-08-10 第一三共株式会社 含氮芳族杂环化合物
RU2481330C2 (ru) * 2008-07-08 2013-05-10 Дайити Санкио Компани, Лимитед Азотсодержащее ароматическое гетероциклическое соединение
CN102149680B (zh) * 2008-07-08 2014-12-10 第一三共株式会社 含氮芳族杂环化合物
WO2010004972A1 (fr) 2008-07-08 2010-01-14 第一三共株式会社 Composé à hétérocycle aromatique contenant de l'azote
JP5461398B2 (ja) * 2008-07-08 2014-04-02 第一三共株式会社 含窒素芳香族ヘテロシクリル化合物
US8648103B2 (en) 2008-07-08 2014-02-11 Daiichi Sankyo Company, Limited Nitrogen-containing aromatic heterocyclyl compound
WO2010003624A2 (fr) 2008-07-09 2010-01-14 Sanofi-Aventis Composés hétérocycliques, leurs procédés de préparation, médicaments comprenant lesdits composés et leur utilisation
WO2010068601A1 (fr) 2008-12-08 2010-06-17 Sanofi-Aventis Hydrate de fluoroglycoside hétéroaromatique cristallin, ses procédés de fabrication, ses procédés d'utilisation et compositions pharmaceutiques le contenant
WO2011023754A1 (fr) 2009-08-26 2011-03-03 Sanofi-Aventis Nouveaux hydrates de fluoroglycoside hétéroaromatiques cristallins, substances pharmaceutiques comprenant ces composés et leur utilisation
US9951087B2 (en) 2009-10-22 2018-04-24 Fibrotech Therapeutics Pty Ltd Fused ring analogues of anti-fibrotic agents
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US11014873B2 (en) 2017-02-03 2021-05-25 Certa Therapeutics Pty Ltd. Anti-fibrotic compounds
US11603349B2 (en) 2017-02-03 2023-03-14 Certa Therapeutics Pty Ltd Anti-fibrotic compounds
CN115057829A (zh) * 2022-05-31 2022-09-16 甘肃联凯生物科技有限公司 一种高纯度唑丙酸的合成方法

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